1. Field of the Invention
The present invention relates to a contrast agent used in magnetic resonance imaging. Further, the present invention relates to a ligand having a novel structure, a novel gadolinium complex having high molecular weight and high self-relaxation rate, and a paramagnetic polynuclear metal complex using the same.
2. Description of the Related Art
Magnetic Resonance Imaging (MRI) is a widely used diagnostic imaging technique. Although excellent soft-tissue images can be obtained by MRI; image quality is determined by contrast enhancement of a contrast agent that is used to improve the image. Consequently, the development of the efficient MRI contrast agents has recently drawn ample attention. Thermodynamically stable and paramagnetic Gd(III) ions bearing a multidentate ligand structure and at least one water molecule are expected to exhibit high water relaxivities and therefore suitable candidates for MRI contrast agents. In addition the MRI contrast agents should have chemical inertness, low in vivo toxicity, and should be completely excreted after the diagnostic examination.
Among the early MRI contrast agents approved for use in humans are ionic Gd(III) complexes such as diethylenetriamine-N,N,N′,N″,N″-pentaacetate, (N-Me-glucamine)2[Gd(DTPA)(H2O)] (Magnevist, Schering) with a self-relaxation rate of approximately 4.7 mM−1s−1 (20 MHz, 298 K) and Neutral Gd(III) complexes, such as [Gd(DTPA-bismethylamide)(H2O)] (Omniscan, Nycomed) with a self-relaxation rate of 4.4 mM−1s−1 (20 MHz, 298 K). However, these contrast agents have the problems of low self-relaxation rate and low thermodynamic stability.
Therefore, studies have been made on the contrast agents having modified DTPA. For example, Korean Patent Publication No. 10-2007-0017621 describes a contrast agent prepared by binding pyridine derivatives at both ends of DTPA, and Korean Patent No. 10-0749087 describes a contrast agent prepared by binding cyclohexane or benzene derivatives at both ends of DTPA. However, since these methods are to improve physical properties attributed to the chemical structure of DTPA, that is, to improve the contrast agent by increasing the water solubility of DTPA, there is a limitation in the improvement of contrast effect.
Further, U.S. Pat. No. 5,508,388 describes a new type of contrast agent prepared by binding amides at both ends of DTPA. However, this patent is suggested to develop a DTPA structure without causing edema, because DTPA causes edema when administered into the human body, and thus it is not concerned with the improvement of contrast effect.
The present inventors have studied to develop various chemical structures for the improvement of contrast effect. As a result, they found that three or more metals are fixed by binding of various metal ions so as to increase the stability in the binding between metal ions and ligands and the self-relaxation rate, thereby completing the present invention.